Green-Kubo expressions for transport coefficients from dissipative particle dynamics simulations revisited.

This article addresses the debate about the correct application of Green-Kubo expressions for transport coefficients from dissipative particle dynamics simulations. We demonstrate that the Green-Kubo expressions are valid provided that (i) the dynamic model conserves the physical property, whose transport is studied, and (ii) the fluctuations satisfy detailed balance. As a result, the traditional expressions used in molecular dynamics can also be applied to dissipative particle dynamics simulations. However, taking the calculation of the shear viscosity as a paradigmatic example, a random contribution, whose strength scales as 1/δt1/2, with δt the time-step, can cause difficulties if the stress tensor is not separated into the different contributions. We compare our expression to that of Ernst and Brito (M. H. Ernst and R. Brito, Europhys. Lett., 2006, 73, 183-189), which arises from a diametrically different perspective. We demonstrate that the two expressions are completely equivalent and find exactly the same result both analytically and numerically. We show that the differences are not due to the lack of time-reversibility but instead from a pre-averaging of the random contributions. Despite the overall validity of Green-Kubo expressions, we find that the Einstein-Helfand relations (D. C. Malaspina et al. Phys. Chem. Chem. Phys., 2023, 25, 12025-12040) do not suffer from the need to decompose the stress tensor and can readily be used with a high degree of accuracy. Consequently, Einstein-Helfand relations should be seen as the preferred method to calculate transport coefficients from dissipative particle dynamics simulations.

Transport coefficients from Einstein-Helfand relations using standard and energy-conserving dissipative particle dynamics methods.

In this article we demonstrate that contrary to general belief, the standard Einstein-Helfand (EH) formulas are valid for the evaluation of transport coefficients of systems containing dissipative and random forces provided that for these mesoscopic systems: (i) the corresponding conservation laws are satisfied, and (ii) the transition probabilities satisfy detailed balance. Dissipative particle dynamics (DPD) and energy-conserving DPD methods (DPDE), for instance, are archetypical of such mesoscopic approaches satisfying these properties. To verify this statement, we have derived a mesoscopic heat flux form for the DPDE method, suitable for the calculation of the thermal conductivity from an EH expression. We have compared EH measurements against non-equilibrium simulation values for different scenarios, including many-body potentials, and have found excellent agreement in all cases. The expressions are valid notably for systems with density- and temperature-dependent potentials, such as the recently developed generalised DPDE method (GenDPDE) [Avalos et al., Phys. Chem. Chem. Phys., 2019, 21, 24891]. We thus demonstrate that traditional EH formulas in equilibrium simulations can be widely used to obtain transport coefficients, provided that the appropriate expression for the associated flux is used.

The Tayside insulin management course: an effective education programme in type 1 diabetes.

AIMS: The Tayside insulin management (TIM) course is an intensive insulin management programme for adults with type 1 diabetes. The aim was to assess its effectiveness. METHODS: Haemoglobin A1c (HbA1c) and body mass index (BMI) from individuals with type 1 diabetes were collected 3 months before, and 6 and 24 months after the programme. The programme involved a full day of education per week for 4 weeks in a row. Quality of life was assessed using the standardised Audit of Diabetes-Dependent Quality of Life (ADDQoL) questionnaire completed both before and 3 months after the course. Subjects were also asked to complete a pre- and postcourse questionnaire gathering information about aspects of their diabetes management. In addition, individual satisfaction with course content and delivery was recorded. RESULTS: Participants had a median reduction in haemoglobin A1c (HbA1c) of 4 mmol/mol (0.4%) after 6 months and 5 mmol/mol (0.5%) 2 years after the course (p < 0.001). Mean daily dose of short-acting insulin decreased from 31.5 (1.9) units to 27.3 (1.9, p < 0.001). There was no significant change in BMI. There was an improvement in all 18 domains of the ADDQoL questionnaire. There was a decrease in hypoglycaemia unawareness from 34.3 ± 47.8% of patients to 8.6 ± 28% (p < 0.001), and a decrease in self-reported lipohypertrophy from 27.8% to 11.1% (p = 0.001). There was a significant reduction in the mean number of diabetic ketoacidosis and severe hypoglycaemic episodes. The number of blood glucose checks changed from 2.8 ± 2.1 to 3.2 ± 1.1 (p = 0.058) per day. Participant satisfaction with all aspects of course content and delivery was high. CONCLUSIONS: TIM is an effective intensive education programme for patients with type 1 diabetes.

Measuring the accuracy of different ways to identify the 'at-risk' foot in routine clinical practice.

AIMS: We aimed to identify which individual risk factors best predict foot ulceration in routine clinical practice and whether an integrated clinical tool is a better screening tool for future foot ulceration. METHODS: Routinely collected clinical information on foot and general diabetes indicators were recorded on the regional diabetes electronic register. Follow-up data on foot ulceration were collected from the same electronic record, the local multidisciplinary foot clinic and community and hospital podiatry paper records. Data were electronically linked to see which criteria best predicted future foot ulceration. RESULTS: Foot risk scores were recorded on 3719 patients (44% female, mean age 59±15years) across community and hospital clinics. Overall, 851 (22.9%) had insensitivity to monofilaments, in 629 (17.2%) both pulses were absent and 184 (4.9%) had a prior ulcer. In multivariate analysis, the strongest predictors of foot ulceration were prior ulcer, insulin treatment, absent monofilaments, structural abnormality and proteinuria and retinopathy. The sensitivity of predicting foot ulceration was 52% for prior ulcer, 61% for absent monofilaments, 75% for 'high risk' on an integrated risk score and 91% for high and moderate risk combined. The corresponding specificities were 99, 81, 89 and 61%. Positive likelihood ratio was 52 for prior ulcer and 6.8 for foot risk, with negative likelihood ratios of 0.48 and 0.15, respectively. CONCLUSIONS: Integrated foot risk scores are more sensitive than individual clinical criteria in predicting future foot ulceration and are likely to be better screening tools, where excluding false negative results is of paramount importance.

Water liquid-vapor equilibria predicted by refined ab initio derived potentials.

Coexistence properties for water near the critical point using several ab initio models were calculated using grand canonical Monte Carlo simulations with multiple histogram reweighting techniques. These models, that have proved to yield a good reproduction of the water properties at ambient conditions, perform rather well, improving the performance of a previous ab initio model. It is also shown that bulk geometry and dipole values, predicted by the simulation, can be used and a good approximation obtained with a polarizable rigid water model but not when polarization is excluded.

Cystic fibrosis-related diabetes.

Diabetes mellitus (DM) has been recognized as a complication of cystic fibrosis (CF) for almost 50 years and commonly develops around 20 years of age. The prevalence increases with age and, with improved survival of those with CF, approaches 30% in certain centres. Its development appears to have a significant impact on pulmonary function and may increase mortality by up to six-fold. Subjects with CF are rarely ketosis-prone and phenotypically lie between Type 1 and Type 2 DM. Microvascular complications are recognized, although paucity of data does not permit a clear description of their natural history. An annual oral glucose tolerance test from the age of 10 years is recommended for screening, but logistical difficulties have led some groups to develop specific algorithms to aid diagnosis. Insulin sensitivity in CF is much debated and may depend upon the degree of glucose intolerance. Insulin resistance occurs in the presence of infection, corticosteroid usage and hyperglycaemia, whilst hepatic insulin resistance is considered an adaptation to CF. There is no universal consensus on the treatment of hyperglycaemia. With increased longevity of individuals with CF, greater numbers will develop diabetes and the diabetes physician is destined to play a greater role in the multidisciplinary CF team.

Mutations in the hepatocyte nuclear factor-1alpha gene are a common cause of maturity-onset diabetes of the young in the U.K.

Mutations in the hepatocyte nuclear factor-1alpha (HNF1alpha) gene have recently been shown to cause maturity-onset diabetes of the young (MODY). We have examined 15 U.K. MODY families for mutations in the coding region of the HNF-1alpha gene. Eight different mutations, three frameshift (P291fsinsC, P379fsdelCT, and A443fsdelCA) and five missense mutations (P129T, R131W, R159W, P519L, and T620I), were identified in eleven families (73%). The previously reported mutation P291fsinsC was found in four pedigrees. A screen of a further 32 probands with early onset (<40 years of age) NIDDM showed the mutation in two additional families. This common mutation was present on at least three different haplotypes, suggesting that its high frequency is due to recurrent mutation rather than a founder effect. We have demonstrated that mutations in the HNF-1alpha gene are a common cause of MODY in U.K. families and result in early onset NIDDM with a progressive clinical course. Mutation-based genetic counseling can now be considered for the majority of patients with MODY.

Outcome of pregnancy in patients with insulin-dependent diabetes mellitus and nephropathy with moderate renal impairment.

This study examines the effect of pregnancy on fetal outcome and maternal renal function in 17 women with Type 1 diabetes mellitus and nephropathy attending a joint diabetic-antenatal clinic between 1985 and 1993. There were 7 successful pregnancies in 6 women with moderate renal impairment, mean pre-pregnancy serum creatinine 165 mumol l-1 (Group 1), and 12 in 11 women with proteinuria and preserved renal function (Group 2). Median gestation of pregnancy was 31 + 3 weeks in Group 1 and 36 + 4 weeks in Group 2 (p < 0.05). All babies in Group 1 required neonatal intensive care for a median of 19 days (range 8-271) as compared to only 5 of 13 in Group 2 whose median stay was 13 (7-17) days (p < 0.05). There was one late death in Group 1. Longitudinal creatinine data in those with moderate renal impairment suggest no systematic adverse long-term effect of pregnancy on maternal renal function, although differing changes in renal function were observed during pregnancy. The generally favourable outcome achieved relied heavily upon neonatal care expertise.

Candidate gene studies in pedigrees with maturity-onset diabetes of the young not linked with glucokinase.

Maturity-onset diabetes of the young (MODY) is a form of non-insulin-dependent diabetes mellitus characterised by an early age of onset and an autosomal dominant mode of inheritance. Only a proportion of cases are due to mutations in the glucokinase gene. We have studied five Caucasian MODY families, including the first MODY family to be described, with five candidate genes implicated in regulation of insulin secretion. The affected subjects showed more marked hyperglycaemia than that found in subjects with glucokinase mutations. We assessed polymorphic markers close to the genes for glucokinase, hexokinase II, adenosine deaminase, pituitary adenylate cyclase-activating polypeptide receptor, and glucagon-like peptide-1 receptor. Linkage analysis with diabetes gave cumulative log of the odds (LOD) scores of less than -3, implying that mutations in these genes are unlikely to provide a major genetic contribution to this form of MODY.

The assay of laminin fragments in serum and urine as an indicator of renal damage induced by toxins.

An ELISA procedure for the assay of laminin fragments in serum and urine is described. Samples from solvent-exposed workers and diabetic patients were studied. In cohorts exposed to perchloroethylene serum and urine laminin fragments were elevated but the urinary N-acetyl-beta-D-glucosaminidase (NAG) was unaffected. The data indicate that the urinary assay may be more specific for renal damage than the serum method. Differences in the excretion of NAG and urinary laminin fragments were observed in the diabetic groups suggesting that the excretion of these two components reflects different stages of severity of the disease.

Presentation, clinical features and outcome in different patterns of atherosclerotic renovascular disease.

Atherosclerotic renovascular disease (ARD) is an increasingly important cause of renal failure. However, important features of the clinical presentation are not fully described, and the outcome after intervention by angioplasty remains controversial. Ninety-four patients with ARD diagnosed at angiography were reviewed. Twenty-four patients were diabetic. Thirty-nine patients had unilateral renal artery stenosis or occlusion (group A), 28 had bilateral stenosis (group B), and 27 had unilateral occlusion plus contralateral occlusion or stenosis (group C). Two years after presentation, actuarial patient survival was 96%, 74.3% and 47.1% in groups A, B and C, respectively (p < 0.001 for all differences); actuarial renal survival in surviving patients was 97.3%, 82.4% and 44.7%, respectively (p < 0.001 for all differences). Percutaneous transluminal balloon angioplasty (PCTA) was performed in 74 patients. Renal function improved in only a minority of cases, but was stable in 73% of nondiabetic patients 12 months after PCTA. Angioplasty was less effective in diabetic subjects, with only 53.3% having stable renal function at 12 months follow-up. Renal and patient survival were strongly related to the initial angiographic findings. In non-diabetic subjects, PCTA resulted in stabilization of renal function for at least one year in nearly three-quarters of cases, which suggests a benefit from intervention in this disease whose natural history is otherwise of progression.

The effects of renzapride, a novel prokinetic agent, in diabetic gastroparesis.

Gastric emptying was measured in 9 diabetic patients with autonomic neuropathy (Group 1) and 8 normal controls (Group 2) on 4 occasions after swallowing placebo, 0.5, 1.0 or 2.0 mg of the newly developed prokinetic drug renzapride given double-blind and in random order. The liquid component of the test meal was labelled with In113m and the solid with Tc99m. Liquid emptying was uni-exponential. Solid emptying comprised an initial lag phase, followed by a linear component. Following placebo, the mean lag phase of solid emptying was 40 +/- 7 (S.E.M.) min in Group 1 and 16 +/- 2 min in Group 2 (P less than 0.01). In Group 1 subjects renzapride reduced the mean lag phase by 20-26 min at all doses (P less than 0.01). No effect was seen in Group 2. The linear rate of solid emptying was similar in both groups (0.9 +/- 0.1 and 1.0 +/- 0.2%/min) and was not altered by renzapride. Mean liquid t1/2 was similar in Groups 1 and 2 after placebo (30 +/- 6 and 29 +/- 4 min, respectively) and was decreased with increasing doses of renzapride in both groups. No adverse effects were encountered in any subjects. Renzapride may be useful in the treatment of diabetic gastroparesis.

Potentiation of hydrocortisone activity in skin by glycyrrhetinic acid.

The enzyme 11 beta-hydroxysteroid dehydrogenase (11 beta-OHSD), which catalyses the conversion of cortisol to the inactive steroid cortisone in man (and corticosterone to 11-dehydrocorticosterone in rodents), was demonstrated by immunohistochemistry in skin biopsy samples from healthy volunteers and from patients with psoriasis and eczema. In-vitro studies confirmed the presence of the enzyme in skin from nude mice and showed that it is inhibited by glycyrrhetinic acid, the major active component of liquorice. By means of the skin vasoconstrictor assay, glycyrrhetinic acid was shown to potentiate the action of hydrocortisone. This work suggests a novel means of targeting glucocorticoid therapy.